GDC-9545 (Giredestrant): A Potent and Orally Bioavailable Selective Estrogen Receptor Antagonist and Degrader with an Exceptional Preclinical Profile for ER+ Breast Cancer

Breast cancer remains a leading cause
of cancer death in women,
representing a significant unmet medical need. Here, we disclose our
discovery efforts culminating in a clinical candidate, 35 (GDC-9545 or giredestrant). 35 is an efficient and
potent selective estrogen receptor degrader (SERD) and a full antagonist,
which translates into better antiproliferation activity than known
SERDs (1, 6, 7, and 9) across multiple cell lines. Fine-tuning the physiochemical properties
enabled once daily oral dosing of 35 in preclinical species
and humans. 35 exhibits low drug–drug interaction
liability and demonstrates excellent in vitro and in vivo safety profiles. At low doses, 35 induces
tumor regressions either as a single agent or in combination with
a CDK4/6 inhibitor in an ESR1Y537S mutant PDX or a wild-type
ERα tumor model. Currently, 35 is being evaluated
in Phase III clinical trials.